Features of Lipid Metabolism in Humanized ApoE Knockin Rat Models

Abstract

Apolipoprotein E (ApoE), an essential plasma apolipoprotein, has three isoforms (E2, E3, and E4) in humans. E2 is associated with type III hyperlipoproteinemia. E4 is the major susceptibility gene to Alzheimer’s disease (AD) and coronary heart disease (CHD). We investigated lipid metabolism and atherosclerotic lesions of novel humanized ApoE knockin (hApoE KI) rats in comparison to wide-type (WT) and ApoE knockout (ApoE KO) rats. The hApoE2 rats showed the lowest bodyweight and white fat mass. hApoE2 rats developed higher serum total cholesterol (TC), total triglyceride (TG), and low- and very low density lipoprotein (LDL-C&VLDL-C). ApoE KO rats also exhibited elevated TC and LDL-C&VLDL-C. Only mild atherosclerotic lesions were detected in hApoE2 and ApoE KO aortic roots. Half of the hApoE2 rats developed hepatic nodular cirrhosis. A short period of the Paigen diet (PD) treatment led to the premature death of the hApoE2 and ApoE KO rats. Severe vascular wall thickening of the coronary and pulmonary arteries was observed in 4-month PD-treated hApoE4 rats. In conclusion, hApoE2 rats develop spontaneous hyperlipidemia and might be suitable for studies of lipid metabolism-related diseases. With the PD challenge, hApoE4 KI rats could be a novel model for the analysis of vascular remodeling.

Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits

“…The results from this study are encouraging and indicate that reducing total APOE levels can effectively prevent the development of AD pathologies; however, it is not clear whether the beneficial outcomes in this study are due to the reduction of APOE4 in astrocytes, neurons or both, which warrants further investigation in future studies. Considering the possibility that depletion of total APOE4 levels may have deleterious side effects 73 – 77 , it would be beneficial to target the specific removal of APOE4 from a certain cell type in an effort to leave the physiological functions of APOE4 largely intact while targeting its pathogenic effects. Although both neuronal and astrocytic APOE4 exert pathogenic effects, our study has shown that neuronal APOE4 has a potent effect on promoting tau pathology and more wide-ranging detrimental effects that have not yet been characterized for astrocytic APOE4, such as promoting tau spreading, myelin and oligodendrocyte deficits and network hyperexcitability.…”

Organotypic Rat Testicular Organoids for the Study of Testicular Maturation and Toxicology

“…The testes tissue was incubated with anti-γ-H2AX (Gamma H2A Histone Family X) ( 25 ) and anti-SYCP3 (Synaptonemal Complex Protein 3 ) ( 26 ) ( Supplementary Table 1 ). For rat testicular cells, the slides were incubated with anti-GATA4 (GATA Binding Protein 4) ( 27 ), anti-VASA (DEAD-Box Helicase 4) ( 28 ), anti-α-SMA(alpha-Smooth Muscle Actin) ( 29 ), anti-3β-HSD (3 Beta-Hydroxysteroid Dehydrogenase) ( 28 ) ( Supplementary Table 1 ). In addition to the antibodies mentioned above, rat organoids were also incubated with anti-Collagen IV ( 30 ), anti-Laminin ( 31 ), anti-Fibronectin ( 32 ), anti-Claudin 11 ( 33 ), anti-UCHL1 (Ubiquitin C -terminal Hydrolase L1), anti-TNP1 (Transition Protein 1) ( 34 ), anti-PRM1 (Protamine 1) ( 35 ), anti-ACR (Acrosin) ( 36 ) and anti-AR (Androgen Receptor) ( 37 ) antibodies overnight at 4°C ( Supplementary Table 1 ).…”

Human ApoE2 Endows Stronger Contractility in Rat Cardiomyocytes Enhancing Heart Function

“…All transgenic rats showed slightly higher tail-cuff readings compared to WT rats. In our previous study [27], we found that hApoE2 rats developed spontaneous hyperlipidemia without plaque formation at age 6 months. The high lipids levels in the vessels might cause vascular problems, such as increased stiffness/decreased elasticity of arterial walls.…”